P729: LANDSCAPE OF GERMLINE PATHOGENIC/ LIKELY PATHOGENIC MUTATIONS INVOLVING DNA REPAIR GENES IN SOLID TUMOR PATIENTS WITH ANTECEDENT OR SUBSEQUENT MYELOID NEOPLASMS
Authors: Kimberly Hein, Sinchita Roy Chowdhuri, Courtney Dinardo, Guillermo Garcia-Manero, Keyur Patel, Mark Routbort, Richard Yang, Beenu Thakral, Guillermo Montalban-Bravo, Sanam Loghavi, L. Jeffrey Medeiros, Kelly Chien, Rajyalakshmi Luthra, Rashmi Kanagal-Shamanna
Journal: HemaSphere (2023)

Background: The 2022 WHO and ICC classifications include well-established entities with alterations involving specific genes leading to particular predilection to myeloid neoplasms. These include MN with germline predisposition without a pre-existing platelet disorder or organ dysfunction (CEBPA, DDX41, TP53), MN with pre-existing platelet disorder (RUNX1, ANKRD26, ETV6) and MN with potential organ dysfunction (that includes numerous subtypes such as GATA2, SAMD9, SAMD9L, telomere biology disorders, BM failure syndromes, Fanconi anemia and many others). In addition, there are cancer predisposing syndromes with gene alterations leading to disrupted DNA repair that tend to be associated with both solid tumors and MN. These involve genes such as CHEK2, BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2. Germline genetic alterations involving these pan-cancer susceptibility genes are likely to be enriched in patients who develop solid tumors (ST) and antecedent/subsequent myeloid neoplasm (MN), including those with therapy-related MN (t-MN)/ MN post-cytotoxic therapy (MN-PCT). To date, the knowledge on the frequencies and spectrum of germline mutations involving pan-cancer susceptibility genes associated with myeloid neoplasms is not known. Aims: The goal of this study was to evaluate the landscape of germline alterations involving cancer predisposition genes (specifically those affecting DNA repair) beyond those implicated in leukemias in a cohort of patients who developed both solid tumors and MNs. Methods: From our database, we identified all patients who had at least 1 ST and MN and underwent comprehensive targeted NGS of ST [mutation (128-gene) and fusion analysis] with matched peripheral blood (PB) as germline, as well as targeted NGS for MN (81-gene). PB sequencing data (at the time of ST) was evaluated for pathogenic (P)/ likely pathogenic (LP) variants in genes implicated in cancer predisposition disorders, including BRCA1, BRCA2, ATM, CHEK1/2, MLH1, MSH2, MSH6, PALB2, PMS2, RB1, TERT, TSC1/2. Clinical data was collected from medical records. Results: Between 2012-2022, there were 77 patients (45 M; 32 F; median age: 71 yrs). The median number of solid tumors per patient was 1 (1-3). In 19 (25%) patients, MN preceded the ST; in 49 (64%) patients, MN developed after cytotoxic therapy for ST (t-MN). In 10 (13%) patients, the tumors were concomitant (within 6 months). Recurrent STs included lung carcinoma [n=10; 9 with adenocarcinoma], followed by gastrointestinal (n=6), soft tissue (n=6), genitourinary (n=6) and others. MNs included: AML [n=17; included 1 pt with APL, 1 with CBFB::MYH11], MDS (n=52), CMML (n=4). Four pts had CML. By somatic NGS studies, 88% of ST cases had mutations; none had fusions. Frequent somatic mutations in ST were TP53 gene (n=26; 34%; six TP53mut pts had concomitant KRAS mutations). In contrast, NGS of MNs showed frequent somatic mutations involving TET2 (n=24), TP53 (n=14), ASXL1 (n=11), BCORL1 (n=7), and DNMT3A (n=6) in decreasing order of frequencies. By matched PB (germline) NGS, 15 (19%) of 77 patients had P/LP variants in cancer predisposition genes noted only in PB [included 11 (22%) with t-MN/MN-PCT]: 5 pts with BRCA2, 5 patients with TP53, 1 with DDX41, BRCA1, PMS2, MSH6 and PALB2. Germline origin was confirmed in a subset using skin biopsy. In 2 more pts, germline VUS involving TP53 and TSC1 were noted. Summary/Conclusion: Germline P/LP variants involving cancer predisposition genes are enriched (19%) in pts with both ST and MN, including t-MN/MN-PCT (22%), warranting a low threshold for initiation of germline testing in these pts. Keywords: MDS, MDS/AML, Familial, Therapy-related AML